Metaplastic sleep regulation in Drosophila determined by microscale circadian neural dynamics

Abstract

The biophysical mechanisms by which circadian clock neurons integrate temporal coding signals to regulate sleep remain elusive. Here, using Drosophila, we identify Rabphilin (Rph) in DN1p clock neurons as a key stabilizer of the metaplasticity setpoint governing circadian regulation of sleep. Rph protein levels are elevated at night relative to daytime and modulate stochastic process of DN1p membrane potential dynamics linked to variability in synaptic activity at connections between DN1p neurons and their downstream postsynaptic partners. We find that Rph acts as a bidirectional regulator of synaptic plasticity thresholds. Under dim nocturnal light stimulation, Rph knockdown permits synaptic potentiation, whereas synthesized Rph introduction induces synaptic depression. In contrast, under optogenetic manipulation mimicking daytime spiking in DN1p neurons, these effects are reversed. We further show that spike-timing-dependent plasticity emerges when postsynaptic spiking is engaged, with nocturnal dim light conditions determining the direction of plasticity. Together, these findings establish a mechanistic link between microscale circadian neural dynamics and hierarchical metaplastic regulation, demonstrating how circadian regulation of sleep dynamically balances stability and adaptive flexibility through circadian setpoints and environmental nocturnal light interactions. Significance StatementWe show that circadian metaplasticity regulates sleep through membrane potential dynamics. Circadian clock neurons implement flexible metaplasticity, whereby the direction can be determined by internal circadian setpoints and interactions with nocturnal environmental light. This mechanism engages spike-timing-dependent plasticity to determine plasticity polarity. Our findings identify membrane potential dynamics as a computational substrate for physiological state control, linking molecular mechanisms to circuit-level circadian regulation of sleep. Together, they reframe sleep regulation as an active metaplastic process that hierarchically integrates microscale circadian neural dynamics to optimize circuit function.